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Wiener klinisches Magazin

, Volume 21, Issue 6, pp 260–269 | Cite as

Gastrointestinale Stromatumoren

Bedeutung der molekularen Diagnostik für Prognose und Therapie
  • Silke CameronEmail author
Pathologie
  • 12 Downloads

Zusammenfassung

Hintergrund

Vor 20 Jahren beschrieben Hirota et al. die Expression einer Rezeptortyrosinkinase des Protoonkogens KIT durch einen besonderen Typ mesenchymaler Tumoren des Gastrointestinaltrakts: den gastrointestinalen Stromatumor (GIST). Seither ist die molekulare Diagnostik auch im Hinblick auf therapeutische Möglichkeiten fortgeschritten.

Fragestellung

Dieser Artikel zeichnet die Bedeutung der unterschiedlichen Tyrosinkinase(TK)-Rezeptor-Mutationen sowie die nachgeschalteten Signalwege bis in den Nukleus und ihre Relevanz für die Pathogenese und Therapie der GIST nach.

Material und Methode

Die gängige internationale Literatur wurde strukturiert zur Beantwortung bisher unklarer Fragen zusammengestellt.

Ergebnisse

Während KIT in unterschiedlichen Zellen exprimiert wird (Cajal-Zellen, hämatopoietischen Stammzellen, Melanozyten, Mastzellen und Keimzellen), entstehen GIST aus Cajal-Zellen (oder deren Vorläufern). Somit muß ein definierter zellulärer Kontext für die Entwicklung von GIST bestehen. Mikro-GIST zeigen bereits die Treibermutation im Tyrosinkinaserezeptor, entwickeln sich jedoch erst zu manifesten GIST bei hoher endogener Expression des Transkriptionsfaktors ETV1. Wie KIT- und PDGFRA-Mutationen schließen sich KRAS- und BRAF-Mutationen gegenseitig aus. KRAS- und BRAF-Mutationen können als nachgeschaltete Mutationen vorkommen. Wildtyp(WT)-GIST mit ihren Unterformen der Succinatdehydrogenase(SDH)-Defizienz sind jedoch gesondert zu betrachten. Ob sekundäre Mutationen unter therapeutischem Selektionsdruck neu entstehen oder – bereits vorhanden – selektiert werden, ist bisher unklar. Sekundäre Mutationen scheinen jedoch erst ab einem bestimmten Expressionsniveau Relevanz zu besitzen. Die Therapie fortgeschrittener GIST ist aufgrund der komplexen genomischen Evolution und der Entwicklung von Resistenzen erschwert.

Schlussfolgerungen

Trotz Ihrer Seltenheit bleiben GIST auch für komplexe Therapiesituationen Modelltumoren.

Schlüsselwörter

Gastrointestinale Tumoren Signaltransduktion Molekulare Pathologie Personalisierte Therapie Imatinib 

Gastrointestinal stromal tumors

Relevance of molecular diagnostics for prognosis and treatment

Abstract

Background

In 1998, Hirota et al. described the expression of a receptor tyrosine kinase of the protooncogene KIT by unique mesenchymal tumors of the gastrointestinal tract: gastrointestinal stromal tumors (GIST). Since then, molecular diagnostics have advanced, also in view of therapeutic options.

Aim

This article retraces the different tyrosine kinase receptor mutations as well as the downstream signaling pathways with subsequent nuclear events and their relevance for the prognosis and treatment of GIST.

Materials and methods

In order to answer previously unclear questions, the international literature is summarized in a structured manner.

Results

Whilst KIT is expressed in different cells (Cajal cells, hematopoietic stem cells, melanocytes, mast cells and germ cells), GIST only originate from Cajal cells (or their precursor cells); thus there should be a defined cellular context for the development of GIST. Micro-GIST already carry the driver mutation in the tyrosine kinase receptor, however, they only develop into manifest GIST if endogenous expression of the transcription factor ETV1 is high. Like KIT and PDGFRA mutations, KRAS and BRAF mutations are mutually exclusive. They can however occur as downstream mutations. Wild-type (WT) GIST with its subgroup “succinate dehydrogenase (SDH) deficiency” has to be viewed separately. Whether secondary mutations develop under therapy or are selected throughout therapy remains unclear. However, secondary mutations themselves seem to only take effect if a minimal expression level is exceeded. Therapeutic options in advanced GIST are limited because of their complex genetic evolution and the development of resistance.

Conclusions

Despite being rare, GIST remain model tumors even for complex therapeutic situations.

Keywords

Gastrointestinal neoplasms  Signal transduction Molecular pathology  Personalized medicine Imatinib 

Notes

Danksagung

Ich danke Herrn Professor Abbas Agaimy, Pathologie Universität Erlangen, für das Korrekturlesen des Manuskripts.

Einhaltung ethischer Richtlinien

Interessenkonflikt

S. Cameron gibt an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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Copyright information

© Springer-Verlag GmbH Austria, ein Teil von Springer Nature 2018

Authors and Affiliations

  1. 1.Klinik für Gastroenterologie und Gastrointestinale OnkologieUniversitätsmedizin GöttingenGöttingenDeutschland

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